Sandbox:Cherry

lab findings

Diagnosis of Cirrhosis

Laboratory findings —

Laboratory abnormalities may be the first indication of cirrhosis.

Common abnormalities include:

Increased serum bilirubin levels

Abnormal aminotransferase levels

Elevated alkaline phosphatase / gamma-glutamyl transpeptidase 

Prolonged prothrombin time 

Elevated international normalized ratio (INR) 

Hyponatremia 

Thrombocytopenia

Liver function tests . .

●Aminotransferases –

Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are usually moderately elevated

AST is more often elevated than ALT

Levels may be normal

●Alkaline phosphatase –

Alkaline phosphatase is usually elevated

High levels may be seen in patients with underlying cholestatic liver disease such as

primary sclerosing cholangitis

primary biliary cirrhosis

●Gamma-glutamyl transpeptidase –

Non specific

Correlates with ALP levels

Higher in CLD due to alcohol use:

Alcohol causes GGT release from hepatocytes

Alcohol induces microsomal GGT in liver

●Bilirubin – Bilirubin levels may be normal or raised

●Albumin – Albumin levels reflect synthetic function of the liver

Serum albumin levels helps grade the severity of cirrhosis

Hypoalbuminemia is non specific for liver disease: heart failure, nephrotic syndrome, protein losing enteropathy, or malnutrition.

●Prothrombin time –  Prothrombin time reflects the degree of hepatic synthetic function.

Worsening coagulopathy correlates with the severity of hepatic dysfunction.

Serum chemistries — 

Hyponatremia is common in patients with cirrhosis and ascites and is related to an inability to excrete free water.

Due to ADH elevation

Reflects poor prognosis

Progressive rise in serum creatinine: hepatorenal syndrome

Hematologic abnormalities — 

Thrombocytopenia:most common

Mechanism of thrombocytopenia:

caused by portal hypertension with congestive splenomegaly: sequesters circulating platelets

Decreased thrombopoietin levels

Leukopenia/neutropenia: due to hypersplenism with splenic margination.

Anemia

Mechanism of anemia:

Acute and chronic gastrointestinal blood loss 

Folate deficiency

Direct toxicity due to alcohol 

Hypersplenism 

Bone marrow suppression ( hepatitis-associated aplastic anemia) 

Anemia of chronic disease (inflammation)

Hemolysis

Other abnormalities — Globulins tend to be increased

Disseminated intravascular coagulation 

Fibrinolysis

Vitamin K deficiency

Dysfibrinogenemia

Insulin resistance: nonalcoholic fatty liver disease

Diabetes:  seen in patients with hemochromatosis

Radiologic findings — Radiologic studies include:

Abdominal ultrasound

Computed tomography scan 

Magnetic resonance imaging

Findings may include:

A liver that appears shrunken, irregular, and nodular.

Evidence of Portal HTN:

varices

Ascites

DIAGNOSIS — 

Abdominal imaging (typically ultrasound) helps:

Evaluate the liver parenchyma

Detects extrahepatic manifestations of cirrhosis

Laboratory tests —  AST to platelet ratio index

FibroTest/FibroSure

Imaging studies —  Findings on abdominal imaging are viewed in light of other signs of cirrhosis, such as physical examination or laboratory test findings.

In addition to evaluating the liver, abdominal imaging may reveal:

Hepatocellular carcinoma

Extrahepatic findings suggestive of cirrhosis:

Ascites

Varices

Splenomegaly

Hepatic or portal vein thrombosis

Imaging may indicate etiology of cirrhosis:

CT

A hypertrophied caudate lobe discovered on computed tomographic (CT) scanning, for example, suggests Budd-Chiari syndrome.

MRI

Decreased signal intensity on magnetic resonance imaging may indicate iron overload from hereditary hemochromatosis.

Ultrasonography –  routinely used during the evaluation of cirrhosis

The first radiologic study obtained due to easy availability.

Provides information about :

appearance of the liver

blood flow within the portal circulation

less expensive than other imaging modalities

No exposure to intravenous contrast or radiation

Noninvasive

well tolerated

widely available

Findings:

Advanced cirrhosis: liver may appear small and nodular

Surface nodularity and increased echogenicity with irregular appearing areas are consistent with cirrhosis

Usually atrophy of the right lobe and hypertrophy of the caudate or left lobes.

Ultrasonography may also be used as a screening test for hepatocellular carcinoma :nodules on ultrasonography warrants further evaluation

Findings of portal hypertension:

 increased diameter of the portal vein

 presence of collateral veins

 decreased flow within the portal circulation on Doppler imaging

Ultrasonography is also useful for detecting splenomegaly, ascites, and portal vein thrombosis.

●Computed tomography – not routinely used in the diagnosis of cirrhosis.

It provides similar information to ultrasonography, but at the expense of radiation and contrast exposure.

CT findings:

Hepatic nodularity 

Atrophy of the right lobe

Hypertrophy of the caudate or left lobes

Ascites 

varices

CT portal phase imaging:

 Patency of the portal vein can be demonstrated

Magnetic resonance imaging – The role of magnetic resonance imaging (MRI) in the diagnosis of cirrhosis is unclear.

 Use is limited by expense

 Poor tolerance of the examination

 Ability to obtain information provided by MRI through other means

reveal iron overload and provide an estimate of the hepatic iron concentration

Magnetic resonance angiography (MRA) is more sensitive than ultrasonography for diagnosing complications of cirrhosis:

 portal vein thrombosis 

CT portal phase imaging, MRA can determine the volume and direction of blood flow in the portal vein.

Elastography – Increasing scarring of the liver is associated with increasing "stiffness" of the tissue.

Nuclear studies –

 Radionuclide testing can be useful in suggesting the diagnosis of cirrhosis:

 99mTc sulfur colloid is normally taken up by cells of the reticuloendothelial system.

Cirrhosis: heterogeneity in the uptake of 99mTc sulfur colloid by the liver and increased uptake by the spleen and bone marrow

Liver biopsy —

The gold standard for diagnosing cirrhosis is:

Examination of an explanted liver, either at autopsy or following liver transplantation, because the architecture of the entire liver can be appreciated.

Cirrhosis is diagnosed with a liver biopsy

Sample of the liver is obtained by:

Percutaneous

Transjugular 

Laparoscopic 

radiographically-guided fine-needle approach.

Liver biopsy is not necessary if the clinical, laboratory, and radiologic data strongly suggest the presence of cirrhosis and if the results would not alter the patient's management.

An example would be a patient with a history of heavy alcohol use who has ascites, severe coagulopathy, and a shrunken, nodular-appearing liver on ultrasonography.

Liver biopsy may be suggestive of etiology:

metabolic causes of cirrhosis include:

hereditary hemochromatosis

nonalcoholic steatohepatitis

Wilson disease

alpha-1 antitrypsin deficiency

rough

Diagnosis of Cirrhosis

Laboratory findings —

Laboratory abnormalities may be the first indication of cirrhosis.

Common abnormalities include:

Increased serum bilirubin levels

Abnormal aminotransferase levels

Elevated alkaline phosphatase / gamma-glutamyl transpeptidase 

Prolonged prothrombin time 

Elevated international normalized ratio (INR) 

Hyponatremia 

Thrombocytopenia

Liver function tests . .

●Aminotransferases –

 Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are usually moderately elevated

 AST is more often elevated than ALT

Levels may be normal

●Alkaline phosphatase –

Alkaline phosphatase is usually elevated

High levels may be seen in patients with underlying cholestatic liver disease such as

primary sclerosing cholangitis

primary biliary cirrhosis

●Gamma-glutamyl transpeptidase –

Non specific

Correlates with ALP levels

Higher in CLD due to alcohol use:

Alcohol causes GGT release from hepatocytes

Alcohol induces microsomal GGT in liver

●Bilirubin – Bilirubin levels may be normal or raised

●Albumin – Albumin levels reflect synthetic function of the liver

Serum albumin levels helps grade the severity of cirrhosis

 Hypoalbuminemia is non specific for liver disease: heart failure, nephrotic syndrome, protein losing enteropathy, or malnutrition.

●Prothrombin time –  Prothrombin time reflects the degree of hepatic synthetic function.

Worsening coagulopathy correlates with the severity of hepatic dysfunction.

Serum chemistries — 

Hyponatremia is common in patients with cirrhosis and ascites and is related to an inability to excrete free water.

Due to ADH elevation

Reflects poor prognosis

progressive rise in serum creatinine: hepatorenal syndrome

Hematologic abnormalities — 

Thrombocytopenia:most common

Mechanism of thrombocytopenia:

caused by portal hypertension with congestive splenomegaly: sequesters circulating platelets

Decreased thrombopoietin levels

Leukopenia/neutropenia: due to hypersplenism with splenic margination.

Anemia

Mechanism of anemia:

Acute and chronic gastrointestinal blood loss 

Folate deficiency

Direct toxicity due to alcohol 

Hypersplenism 

Bone marrow suppression ( hepatitis-associated aplastic anemia) 

Anemia of chronic disease (inflammation)

 Hemolysis

 Other abnormalities — Globulins tend to be increased

Disseminated intravascular coagulation 

Fibrinolysis

Vitamin K deficiency

Dysfibrinogenemia

Insulin resistance: nonalcoholic fatty liver disease

Diabetes:  seen in patients with hemochromatosis

Radiologic findings — Radiologic studies include:

 Abdominal ultrasound

 Computed tomography scan 

 Magnetic resonance imaging

 Findings may include:

 A liver that appears shrunken, irregular, and nodular.

 Evidence of Portal HTN:

 varices

 Ascites

DIAGNOSIS — 

Abdominal imaging (typically ultrasound) helps:

 Evaluate the liver parenchyma

Detects extrahepatic manifestations of cirrhosis

Laboratory tests —  AST to platelet ratio index

 FibroTest/FibroSure

Imaging studies —  Findings on abdominal imaging are viewed in light of other signs of cirrhosis, such as physical examination or laboratory test findings.

 In addition to evaluating the liver, abdominal imaging may reveal:

Hepatocellular carcinoma

Extrahepatic findings suggestive of cirrhosis:

 ascites,

 varices,

 splenomegaly,

hepatic or portal vein thrombosis. 

Diagnosis

Diagnosis

-USG: first line investigation of choice

 Ultrasound with colour Doppler imaging  measures changes in blood flow due to portal hypertension

excludes biliary obstruction in jaundiced patients

safe

cheap 

Noninvasive

Early signs of cirrhosis in B-ultrasonography include:

inhomogeneity of the hepatic tissue

Irregularity of the hepatic surface 

enlargement of the caudate lobe 

Splenomegaly due to portal HTN

The diagnostic evaluation of cirrhosis with ultrasonography is based on the direct relation between the extent of fibrosis and the ultrasonographically determined degree of liver stiffness.

 ultrasonography can rule cirrhosis in or out in over 90% of cases , its findings are less than 100% specific because of occasional in -correct measurements and false-positive findings

-Computed tomography (CT) scanning :

Classical appearances in some diseases, eg, haemochromatosis: Heaptic density increases due to excess iron deposition

-Magnetic resonance imaging (MRI)

Helps differentiaiting focal lesions based on their nature:

hepatic metastases

nodular regeneration

-endoscopic retrograde cholangiopancreatography: in  diagnosis of sclerosing cholangitis

-Liver biopsy

Cirrhosis is primarily a histological diagnosis 

-Prerequisites:

normal INR and platelet count.

-Risks

Haemorrhage

biliary peritonitis

haematoma

perforation of other viscera

mortality rates of between 0.01% and 0.1%

 May be performed in combination with either ultrasound or CT.

-Patients with moderate coagulopathy: 

Plugged liver biopsy : injection of gelatin sponges or metal

coils down the tract after biopsy.

Laparoscopic liver biopsy  performed on a sedated patient with moderate coagulopathy

Advantage: allows direct visualisation of the liver

-patients with severe clotting disorders: Transjugular liver biopsy : 

 risk of intraperitoneal bleed is  less

  Disadvantages:

 biopsies are small: multiple biopsies required 

 taken 'blindly'

Findings in liver biopsy

Fibrous septa between the portal fields 

Nodules- micronodular, macronodular 

In advanced liver disease approaching the stage of cirrhosis: 

thrombocytopenia

Impaired hepatic biosynthesis

Low concentration of albumin

Low concentration of cholinesterase

elevation of the international normalized ratio [INR])

impairment of the detoxifying function of the liver : e.g., elevated bilirubin concentration

transaminase levels are generally in the normal range or only mildly elevated.

Ancillary studies include:

Upper abdominal ultrasonography

Gastroscopy

Esophagogastroduo -denoscopy (EGD) : used to demonstrate eso -phageal varices

 Assessment of bleeding  

Performed in all cases of cirrhosis

Liver biopsy is contraindicated, if the diagnosis of cirrhosis has been clearly established

from the clinical findings and imaging:

evidence of decompensation, with ascites

Labs indicating impaired hepatic biosynthesis

Liver biopsy is indicated :

etiology of liver disease is unclear 

stage cannot be determined: length of punch cylinders used for liver biopsy should be atleast 15 mm long, and at least 10 portal fields should be examined per sectional level

diagnosis in doubt

if the biopsy is expected to yield information about the cause of cirrhosis that will affect the treatment choice

Noninvasive diagnostic evaluation of cirrhosis

Laboratory-based methods: 

Routine liver function tests

Hyaluronic acid concentration

AST-to-platelet ratio index: (APRI) is easily calculated as the quotient of the AST

(GOT)

Platelet count: screening index for advanced fibrosis and cirrhosis

Transient elastography and the acoustic radiation force impulse (ARFI) technique are now well-established methods for the staging of fibrosis in various liver diseases   -USG: first line investigation of choice

Ultrasound with colour Doppler imaging  measures changes in blood flow due to portal hypertension

excludes biliary obstruction in jaundiced patients safe cheap Noninvasive

Early signs of cirrhosis in B-ultrasonography include:

inhomogeneity of the hepatic tissue Irregularity of the hepatic surface enlargement of the caudate lobe Splenomegaly due to portal HTN

-Computed tomography (CT) scanning : Classical appearances in some diseases, eg, haemochromatosis: Heaptic density increases due to excess iron deposition

-Magnetic resonance imaging (MRI) Helps differentiaiting focal lesions based on their nature: hepatic metastases nodular regeneration

-endoscopic retrograde cholangiopancreatography: in diagnosis of sclerosing cholangitis.

-Liver biopsy Cirrhosis is primarily a histological diagnosis.

-Prerequisites: normal INR and platelet count.

-Risks Haemorrhage

biliary peritonitis

haematoma

perforation of other viscera

mortality rates of between 0.01% and 0.1%

May be performed in combination with either ultrasound or CT.

-Patients with moderate coagulopathy: Plugged liver biopsy : injection of gelatin sponges or metal coils down the tract after biopsy.

Laparoscopic liver biopsy performed on a sedated patient with moderate coagulopathy Advantage: allows direct visualisation of the liver

-patients with severe clotting disorders: Transjugular liver biopsy :

risk of intraperitoneal bleed is  less

 Disadvantages:
biopsies are small: multiple biopsies required 
taken 'blindly' 

Findings in liver biopsy Fibrous septa between the portal fields Nodules- micronodular, macronodular

In advanced liver disease approaching the stage of cirrhosis: thrombocytopenia Impaired hepatic biosynthesis Low concentration of albumin Low concentration of cholinesterase elevation of the international normalized ratio [INR])

impairment of the detoxifying function of the liver : e.g., elevated bilirubin concentration
transaminase levels are generally in the normal range or only mildly elevated. 

Findings in liver biopsy

Fibrous septa between the portal fields 

Nodules- micronodular, macronodular 

In advanced liver disease approaching the stage of cirrhosis: 

thrombocytopenia

Impaired hepatic biosynthesis

Low concentration of albumin

Low concentration of cholinesterase

Elevation of the international normalized ratio [INR])

Impairment of the detoxifying function of the liver : e.g., elevated bilirubin concentration

transaminase levels are generally in the normal range or only mildly elevated.

Ancillary studies include:

Upper abdominal ultrasonography

Gastroscopy

Esophagogastroduo -denoscopy (EGD) : used to demonstrate eso -phageal varices

Assessment of bleeding  

Performed in all cases of cirrhosis

Liver biopsy is contraindicated, if the diagnosis of cirrhosis has been clearly established

from the clinical findings and imaging:

Evidence of decompensation, with ascites

Labs indicating impaired hepatic biosynthesis

Liver biopsy is indicated :

Etiology of liver disease is unclear 

Stage cannot be determined: length of punch cylinders used for liver biopsy should be atleast 15 mm long, and at least 10 portal fields should be examined per sectional level

Diagnosis in doubt

If the biopsy is expected to yield information about the cause of cirrhosis that will affect the treatment choice

Noninvasive diagnostic evaluation of cirrhosis

Laboratory-based methods: 

Routine liver function tests

Hyaluronic acid concentration

AST-to-platelet ratio index: (APRI) is easily calculated as the quotient of the AST

(GOT)

Platelet count: screening index for advanced fibrosis and cirrhosis

Transient elastography and the acoustic radiation force impulse (ARFI) technique are now well-established methods for the staging of fibrosis in various liver diseases

Is Liver Biopsy the Gold Standard

in the Diagnosis of Cirrhosis?

Liver biopsy is the gold standard in the diagnosis of cirrhosis, it is an imperfect test.

It is an invasive procedure with complications:

Sampling errors

Death

Measurement of hepatic venous pressure gradient (HVPG):

Indirect measure of sinusoidal pressure obtained through hepatic vein catheterization, has a greater diagnostic accuracy than liver biopsy.

Very accurate in predicting the development of disease progression and the presence of significant fibrosis.

HVPG measurement of 6 mmHg or greater indicates the presence of cirrhosis.

HVPG addresses a larger area of hepatic parenchyma than liver biopsy, since the pressure obtained is

the average pressure of many sinusoids, thus reducing the possibility of sampling error due to

the presence of fibrosis heterogeneity within the diseased liver.

Noninvasive tests including serum markers, ultrasound, and liver and/or spleen stiffness measurements have become important tools in ruling in or excluding cirrhosis with a high diagnostic accuracy and may substitute for liver biopsy in the diagnosis of cirrhosis.

 Laboratory findings —

Laboratory abnormalities may be the first indication of cirrhosis.

 Common abnormalities include:

 Increased serum bilirubin levels

abnormal aminotransferases 

elevated alkaline phosphatase/gamma-glutamyl transpeptidase 

 prolonged prothrombin time 

elevated international normalized ratio (INR) 

Hyponatremia 

Thrombocytopenia

Cherry

Physical Examination

Normal versus Abnormal Barium study of esophagus with varices

GIF maker

Liver Cirhhosis
Source:Wikimedia commons

Spider angiomata
Source:Wikimedia commons

Spider angiomata
Source:Wikimedia commons

Physical Examination

• Physical examination of patients with cirrhosis is usually remarkable for: jaundice, spider angiomata, ascites, asterixis, spleenomegaly and palmar erythema.

Appearance of the Patient

• Patients with cirrhosis usually appear weak due to constitutional symptoms such as weight loss, anorexia and muscle atrophy. Yellowish discoloration of skin and abdominal distension may also be present due to ascites.

• Normal/low blood pressure with normal pulse pressure.

Skin

• Jaundice : yellow discoloration of the skin, eyes, and mucus membranes due to increased bilirubin (at least 2-3 mg/dL or 30 mmol/L). Urine may also appear dark.
• Pallor
• Bruises
• Palmar erythema on the thenar and hypothenar eminences, due to altered sex hormone metabolism.
• Spider angiomata: Increased estradiol levels lead to the formation of vascular lesions consisting of central arterioles surrounded by smaller vessels  
• Telangiectasias or spider veins: small dilated blood vessels near the surface of the skin.

HEENT

• Abnormalities of the head/hair may include thinning of hair on the scalp due to hyperestrogenism
• Kayser-Fleischer rings : dark rings that appear to encircle the iris of the eye in patients with Wilson's disease.
• Parotid gland enlargement
• Fetor hepaticus: severe portal-systemic shunting leads to increased levels of dimethyl sulfide leads to a sweet pungent smell in the breath

Abdomen

• Inspection:
  • Abdominal distension
  • Caput medusae

• Palpation:
  • Fluid wave
  • Hepatomegaly may be present in initial stages. The liver may also be normal or shrunken.
  • Spleenomegaly may be present in patients with cirrhosis from nonalcoholic etiologies, due to portal hypertension

• Percussion:
  •  Flank dullness may be present due to ascites (needs approximately 1500ml for detection)

• Auscultation:
  • Cruveilhier-Baumgarten murmur: venous hum that may be present in patients with portal hypertension.
    • Mechanism: due to collateral connections between remnant of the umbilical vein and the portal system
    • Location: Epigastrium
    • Exacerbating factors: Valsalva maneuver
    • Diminished by: application of pressure on the skin above the umbilicus

Genitourinary

• Testicular atrophy 
• Inversion of the normal male pubic hair pattern

Neuromuscular

• Hepatic encephalopathy may have signs of:
  • Alteration of mental status
  • Confusion
  • Coma
• Asterixis (bilateral but asynchronous flapping motions of outstretched, dorsiflexed hands) is seen in patients with hepatic encephalopathy.

Extremities

• edema of the lower extremities
• Muscle atrophy
• Nail changes:
  • Muehrcke nails: paired horizontal white bands separated by normal color due to hypoalbuminemia
  • Terry nails: the proximal two-thirds of the nail plate appears white, whereas the distal one-third is red due to hypoalbuminemia
  •  Clubbing:  the angle between the nail plate and proximal nail fold is greater than 180 degrees
  • Severe clubbing:
    • "Drum stick" appearance of distal fingers
    • Hypertrophic osteoarthropathy: chronic proliferative periostitis of the long bones
  • Dupuytren's contracture may cause flexion deformities of the fingers: This occurs due to shortening and thickening of the palmar fascia, due to collagen deposition and fibroblastic proliferation.
  • Asterixis in cases with hepatic encephalopathy

Chest findings 

• Gynecomastia: due to increased estradiol levels
• Loss of chest or axillary hair

Other findings

• Hemorrhoids
• Hematemesis
• Melena

History

Psychosocial history

• Past history of abuse

Past Medical history

• History of

Menstrual history

• History of

Family history

• Family history of:

Medication history

• History of medication use should be obtained as many drugs such as opioids cause constipation as a side effect.

Causes

Drugs and Toxins	Infections	Autoimmune	Metabolic	Biliary obstruction(Secondary bilary cirrhosis)	Vascular	Miscellaneous
Alcohol	Hepatitis B	Primary Biliary Cirrhosis	Wilson's disease	Cystic fibrosis	Chronic RHF	Sarcoidosis
Methotrexate	Hepatitis C	Autoimmune hepatitis	Hemochromatosis	Biliary atresia	Budd-Chiari syndrome	Intestinal bypass operations for obesity
Isoniazid	Schistosoma japonicum	Primary Sclerosing Cholangitis	Alpha-1 antitrypsin deficiency	Bile duct strictures	Veno-occlusive disease	Cryptogenic: unknown
Methyldopa			Porphyria	Gallstones
			Glycogen storage diseases (such as Galactosaemia, Abetalipoproteinaemia)

Cirrhosis

Pathophysiology

• When an injured issue is replaced by a collagenous scar, it is termed as fibrosis.
• When fibrosis of the liver reaches an advanced stage where distortion of the hepatic vasculature also occurs, it is termed as cirrhosis of the liver.
• The cellular mechanisms responsible for cirrhosis are similar regardless of the type of initial insult and site of injury within the liver lobule.
• Viral hepatitis involves the periportal region, whereas involvement in alcoholic liver disease is largely pericentral.
• If the damage progresses, panlobular cirrhosis may result.
• Cirrhosis involves the following steps:
  • Inflammation
  • Hepatic stellate cell activation
  • Angiogenesis
  • Fibrogenesis
• Kupffer cells are hepatic macrophages responsible for Hepatic Stellate cell activation during injury.
• The hepatic stellate cell (also known as the perisinusoidal cell or Ito cell) plays a key role in the pathogenesis of liver fibrosis/cirrhosis.
• Hepatic stellate cells(HSC) are usually located in the subendothelial space of Disse and become activated to a myofibroblast-like phenotype in areas of liver injury.
• Collagen and non collagenous matrix proteins responsible for fibrosis are produced by the activated Hepatic Stellate Cells(HSC).
• Hepatocyte damage causes the release of lipid peroxidases from injured cell membranes leading to necrosis of parenchymal cells.
• Activated HSC produce numerous cytokines and their receptors, such as PDGF and TGF-f31 which are responsible for fibrogenesis.
• The matrix formed due to HSC activation is deposited in the space of Disse and leads to loss of fenestrations of endothelial cells, which is a process called capillarization.
• Cirrhosis leads to hepatic microvascular changes characterised by
  •  formation of intra hepatic shunts (due to angiogenesis and loss of parenchymal cells) 
  • hepatic endothelial dysfunction
• The endothelial dysfunction is characterised by
  • insufficient release of vasodilators, such as nitric oxide due to oxidative stress
  • increased production of vasoconstrictors (mainly adrenergic stimulation and activation of endothelins and RAAS)
• Fibrosis eventually leads to formation of septae that grossly distort the liver architecture which includes both the liver parenchyma and the vasculature. A cirrhotic liver compromises hepatic sinusoidal exchange by shunting arterial and portal blood directly into the central veins (hepatic outflow). Vascularized fibrous septa connect central veins with portal tracts leading to islands of hepatocytes surrounded by fibrous bands without central veins.
• The formation of fibrotic bands is accompanied by regenerative nodule formation in the hepatic parenchyma.
• Advancement of cirrhosis may lead to parenchymal dysfunction and development of portal hypertension.
• Portal HTN results from the combination of the following:
  • Structural disturbances associated with advanced liver disease account for 70% of total hepatic vascular resistance.
  •  Functional abnormalities such as endothelial dysfunction and increased hepatic vascular tone account for 30% of total hepatic vascular resistance.

Pathogenesis of Cirrhosis due to Alcohol:

• More than 66 percent of all American adults consume alcohol.
• Cirrhosis due to alcohol accounts for approximately forty percent of mortality rates due to cirrhosis.
• Mechanisms of alcohol-induced damage include:
  • Impaired protein synthesis, secretion, glycosylation
• Ethanol intake leads to elevated accumulation of intracellular triglycerides by:
  • Lipoprotein secretion
  • Decreased fatty acid oxidation
  • Increased fatty acid uptake
• Alcohol is converted by Alcohol dehydrogenase to acetaldehyde.
• Due to the high reactivity of acetaldehyde, it forms acetaldehyde-protein adducts which cause damage to cells by:
  • Trafficking of hepatic proteins
  • Interrupting microtubule formation
  • Interfering with enzyme activities
• Damage of hepatocytes leads to the formation of reactive oxygen species that activate Kupffer cells.
• Kupffer cell activation leads to the production of profibrogenic cytokines that stimulates stellate cells.
• Stellate cell activation leads to the production of extracellular matrix and collagen.
• Portal triads develop connections with central veins due to connective tissue formation in pericentral and periportal zones, leading to the formation of regenerative nodules.
• Shrinkage of the liver occurs over years due to repeated insults that lead to:
  • Loss of hepatocytes
  • Increased production and deposition of collagen

Pathology

• There are four stages of Cirrhosis as it progresses:
  • Chronic nonsuppurative destructive cholangitis - inflammation and necrosis of portal tracts with lymphocyte infiltration leading to the destruction of the bile ducts.
  • Development of biliary stasis and fibrosis
• Periportal fibrosis progresses to bridging fibrosis
• Increased proliferation of smaller bile ductules leading to regenerative nodule formation.

Classification

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Charmaine Patel, M.D. [2]

Overview

Cirrhosis of the liver can be classified using two methods; classification based on etiology, and classification based on morphology. Currently, classifying cirrhosis based on morphology is not used, as it requires an invasive procedure to examine the gross appearance of the liver, and it provides little diagnostic value. Classifying cirrhosis according to etiology is a more accepted form of classification, as it can be attained through non-invasive laboratory testing, and has a higher diagnostic value.

Classification Based on Etiology

Cirrhosis can be classified by its etiology. This is the most widely accepted method of classification.

Alcoholic Cirrhosis

This is the most common cause of cirrhosis, and is caused by continuous and prolonged alcohol abuse. The American Academy of Family Physicians estimate that 60-70 percent of all cases of cirrhosis are a result of alcohol abuse.

Post-Necrotic Cirrhosis

This type of cirrhosis occurs after a massive event causes liver cell death. Viral hepatitis is the most common cause for this type of cirrhosis. Agents that are toxic to the liver can also cause this type of cirrhosis, as well as certain types of carcinomas.

Biliary Cirrhosis

This type of cirrhosis results from any diseases that cause biliary obstruction. There is usually a blockage in the bile duct and there may also be inflammation. The excess bile in the liver causes tissue destruction. It commonly results in jaundice.

Cardiac Cirrhosis

This type of cirrhosis is caused by congestive heart failure causing poor circulation of oxygenated blood to the liver. This results in liver cell death, and the subsequent replacement of dead cells by fibrous tissue.

Genetic Disorder

This is when the cirrhosis is caused by a genetic disorder such as hemochromatosis, Wilson's disease, or alpha-1 antitrypsin deficiency.

Malnutrition

This category contains cirrhosis caused by various forms of malnutrition, particularly chronic starvation.

Classification Based on Morphology

Cirrhosis has historically been classified upon the nodular morphology that is seen on upon the gross appearance of the liver. Accurate assessment of the liver morphology can only be obtained through surgery, biopsy, or autopsy, therefore more recently, more non-invasive means of classifying and determining the causes of cirrhosis are used.

Micronodular	Macronodular	Mixed
Micronodular cirrhosis is characterized by nodules that are less than 3mm in diameter	Macronodular cirrhosis is characterized by nodules that are more than 3mm in diameter	Micronodular cirrhosis can often progress into macronodular cirrhosis. During this transformation, a mixed form of cirrhosis may be seen.
Causes: Alcohol Hemochromatosis Cholestatic causes of cirrhosis Hepatic venous outflow obstruction Nutritional causes of cirrhosis	Causes: Chronic viral hepatitis Hemochromatosis Wilson's disease Post-necrotic cirrhosis	Mixed nodular cirrhosis is also seen in Indian childhood cirrhosis.

Video codes

Normal video

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Video in table

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Floating video

Title

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Redirect

1. REDIRECTEsophageal web

synonym website

https://mq.b2i.sg/snow-owl/#!terminology/snomed/10743008

Image

Normal versus Abnormal Barium study of esophagus with varices

Image to the right

C. burnetii, the Q fever causing agent

Image and text to the right

<figure-inline><figure-inline><figure-inline><figure-inline><figure-inline></figure-inline></figure-inline></figure-inline></figure-inline></figure-inline> Recent out break of leptospirosis is reported in Bronx, New York and found 3 cases in the months January and February, 2017.

Gallery

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  Histopathology of a pancreatic endocrine tumor (insulinoma). Source:https://librepathology.org/wiki/Neuroendocrine_tumour_of_the_pancreas

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  Histopathology of a pancreatic endocrine tumor (insulinoma). Chromogranin A immunostain. Source:https://librepathology.org/wiki/Neuroendocrine_tumour_of_the_pancreas

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  Histopathology of a pancreatic endocrine tumor (insulinoma). Insulin immunostain. Source:https://librepathology.org/wiki/Neuroendocrine_tumour_of_the_pancreas

References

REFERENCES